Therapeutic agents for treating pain, inflammation, and fever include analgesics, anti-inflammatories, and antipyretics. Non-steroidal anti-inflammatory drugs (NSAID's) are one type of such therapeutic agents. They include propionic acid derivatives, acetic acid derivatives, fenamic acid derivatives, biphenylcarbodylic acid derivatives, oxicams, and cyclooxygenase-2 (COX-2) selective NSAID's.
Propionic acid derivatives include for example ibuprofen, naproxen, and ketoprofen. Ibuprofen in particular is a widely used, well known NSAID possessing analgesic and antipyretic properties. It has been commercially available as an over-the-counter drug in many forms for several years. Ibuprofen is chemically known as 2-(4-isobutylphenyl)-propionic acid.
Immediate release NSAID's are typically administered about every 4 to 6 hours. Typically, a daily dose of NSAIDs range from about 50 to about 2000 milligrams, preferably from about 100 to 1600 and most preferably from about 200 to about 1200 milligrams.
Many other active ingredients are administered more frequently due to their relatively shorter duration. For example, the therapeutically effective plasma concentration of the decongestant phenylephrine hydrochloride is about 2.5 hours±0.7 hours, and thus it is typically administered every 2 to 4 hours.
In order to administer a single product containing an NSAID and another active ingredient having a pharmaceutically suitable plasma concentration that is shorter in duration, it would be necessary to modify the release of the latter. It is well-known to reduce the rate of release of a drug or other active ingredient from a dosage form into the gastrointestinal (“g.i.”) fluids of a patient, especially in order to provide prolonged action of the drug in the body.
The rate at which an orally delivered drug reaches its site of action in the body depends on a number of factors, including the rate and extent of drug absorption into the blood through the g.i. mucosa. However, before a drug can be absorbed into the blood, it must first be dissolved in the g.i. fluids. For many drugs, absorption across the g.i. membranes is relatively rapid compared to their dissolution in the g.i. fluids, which thereby renders the dissolution of the drug as the rate limiting step in drug absorption. Therefore, a formulator may effectively control the rate of drug absorption into the blood by modifying the drug's rate of dissolution.
Because the onset and duration of the therapeutic efficacy of drugs vary widely, as do their respective absorption, distribution, metabolism, and elimination, it is known to modify the release of different drugs in different ways, or to have a first drug immediately released from the dosage form, while a second drug is released in a “modified” manner, e.g., either delayed or controlled.
Well known mechanisms by which a dosage form can deliver a drug at a modified rate (e.g. sustained, prolonged, extended or retarded release) include diffusion, erosion, and osmosis. It is often practical to design dosage forms that use a combination of the above mechanisms to achieve a particularly desirable modified release profile for a particular active ingredient.
Disadvantageously, many modified release applications employ solid dosage units having a final large size and weight. The administration of such dosage units presents a problem especially to those patients with difficulty swallowing, such as children and the elderly. Therefore, it is further desirable to provide such modified release medicines either in a chewable or orally disintegratable solid form or a liquid form.
Oral liquid forms have been commonly used for many years to deliver medication with an immediate release profile. See e.g., U.S. Pat. Nos. 5,374,659; 4,788,220; 4,975,465; and 5,183,829. However, the incorporation of a modified release medication into a liquid dosage form presents significant formulation challenges. In particular, coated or chemically bonded particles are typically employed to carry the modified release portion of the drug. For example, U.S. Pat. No. 5,980,882 discloses the use of a drug-resin complex along with a chelating agent for delaying the release rate of the drug. U.S. Pat. No. 4,847,077 discloses the use of water-permeable diffusion barrier coatings on drug-resin complex particles in order to provide a prolonged continuous release of the drug.
The properties of such particles, as well as those of the matrix or suspension medium between them, must be compatible so that the particles can be maintained in a uniformly dispersed state. A particular challenge is the prevention of a premature release of drug from the particles into the matrix or suspension medium during the storage life of the dosage form prior to ingestion by a patient. Additionally, the maintenance of the desired dissolution profile as well as the desired dose uniformity of the dosage form throughout its shelf-life are additional challenges to be addressed in formulating an oral, modified release product. For example, the modified release coating of a drug particle can be compromised through several means including the physical act of compression or through chemical incompatibility with another ingredient, i.e., an active ingredient or an excipient. Disadvantageously, these issues are often encountered when formulating a product containing, for example, an immediate release ibuprofen and a modified release second active ingredient, such as phenylephrine, due to the interaction between the ibuprofen and the modified release coating agents known in the art. Chemical incompatibility of two materials in a dosage form can further be exacerbated in unfavorable conditions such as high moisture environments. These types of conditions are simulated in accelerated stability studies, which are required by regulatory agencies such as the Food and Drug Administration (FDA) for drug products.
United States Patent Application 20060057205 discloses liquid dosage forms comprising phenylephrine and at least a second drug such as an analgesic, wherein the dosage form comprises particles of a complex of both drugs with an ion-exchange resin and wherein the particles are coated with a modified release coating such as a polymethacrylate. However, we have found that uncoated propionic acid derivatives such as ibuprofen can interact with semipermeable modified release coatings, such as those containing ethyl cellulose and polymethacrylate. Deleteriously, this interaction often compromises the release rate and the intended modified release properties of the coated drug.
Copending U.S. Patent Application Ser. No. 60/860,260 discloses liquid pharmaceutical dosage forms comprising a first active ingredient, such as an NSAID, and ion exchange resin particles having a second active ingredient bound thereon to form drug-resin complex particles. The drug-resin complex particles are coated first with a semi-permeable coating layer, and then coated with a protective coating layer. This dosage form permits the second active ingredient to be released in a modified release manner such that the duration of the therapeutic effect of the second active ingredient is substantially the same as the duration of the therapeutic effect of the first active ingredient.
U.S. Pat. Nos. 6,228,398 and 7,157,100 disclose solid dosage forms in which active ingredients are released in both an immediate release and modified release manner. However, the dosage forms disclosed in these patents are not always effective for preventing an interaction between the active ingredient in the immediate release portion and the coatings on the modified release portion.
Therefore, it would be desirable to have a modified release solid or semi-solid dosage form containing a first active ingredient, such as ibuprofen, and modified release particles of another active ingredient, such as phenylephrine, which is not only palatable, but is also in a stable form that guarantees the required release profile after administration. In particular, it would further be desirable to have such a solid or semi-solid analgesic product that provided both an immediate release dose of the ibuprofen and a modified release dose of the second active ingredient to the user without interaction between the ibuprofen and the modified release coating.